A Unique Case of CSF3R-Mutated Chronic Neutrophilic Leukemia with Thrombocytosis

Chronic neutrophilic leukemia (CNL) is a well-recognized, extremely rare myeloproliferative neoplasm (MPN) with only ~200 reported cases until 2017. The current WHO diagnostic criteria include leukocytosis of ≥ 25 x 10⁹/L with ≥ 80% neutrophils/bands, < 10% circulating neutrophil precursors and <1% blasts (<5% bone marrow blasts). Exclusion criteria includes dysplasia, or clinical/molecular diagnosis of other MPN. The WHO classification was updated in 2016 to include CSF3R T618I and other activating mutations in CSF3R as diagnostic. SETBP1 and ASXL1 mutations are frequent but unspecific in CNL and appear to be of prognostic significance. Hepatosplenomegaly and a hypercellular bone marrow with marked granulocytic hyperplasia are common in CNL, but thrombocytosis has not been reported previously.

We report a 72-year-old man with past medical history of hypertension and hepatitis C status post-treatment, who presented with WBC 38.4k/cmm, Hgb 6.3g/dl, MCV 102 fl and platelet count of 2601k/cmm. Reactive etiology of thrombocytosis was ruled out. Peripheral blood smear revealed rare blasts. Bone marrow biopsy was hypercellular (60-80%) with M:E ratio of 10:1, granulocytic and megakaryocytic hyperplasia, clustering of dyspoietic megakaryocytes, no erythroid or myeloid dysplasia and minimal patchy reticulin fibrosis suggestive of primary MPN. Chromosome analysis showed normal karyotype of 46 XY. Molecular studies were negative for BCR-ABL, JAK-2 V617F, CALR and MPL, Next Generation Sequencing revealed mutations in the CSF3R gene (Q781* and T618I) and concurrent inactivating ASXL1-G646fs*12 and activating U2AF1-Q157P mutations. These findings were compatible with a diagnosis of CNL.

We describe an unusual case of CNL confirmed by CSF3R gene mutations (T618I and Q781*) with significant thrombocytosis and without splenomegaly. Although the T618I mutation has commonly been reported in CNL, to the best of our knowledge, the Q781* mutation is novel in CNL, and has only been reported before in severe congenital neutropenia (SCN). Association of Q781* mutation in CSF3R gene with significant thrombocytosis in our patient needs further investigation.